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chromatin conformation

Rainer Malik, Martin Dichgans
Stroke, ischemic stroke and subtypes of ischemic stroke display substantial heritability. Compared to related vascular conditions, the number of established risk loci reaching genome-wide significance for association with stroke is still in the lower range, particularly for etiological stroke subtypes such as large artery atherosclerotic stroke or small vessel stroke. Nevertheless, for individual loci substantial progress has been made in determining the specific mechanisms mediating stroke risk. In this review, we present a roadmap for functional follow-up of common risk variants associated with stroke...
March 15, 2018: Cardiovascular Research
Oana Ursu, Nathan Boley, Maryna Taranova, Y X Rachel Wang, Galip Gurkan Yardimci, William Stafford Noble, Anshul Kundaje
Motivation: The three-dimensional organization of chromatin plays a critical role in gene regulation and disease. High-throughput chromosome conformation capture experiments such as Hi-C are used to obtain genome-wide maps of 3D chromatin contacts. However, robust estimation of data quality and systematic comparison of these contact maps is challenging due to the multi-scale, hierarchical structure of chromatin contacts and the resulting properties of experimental noise in the data. Measuring concordance of contact maps is important for assessing reproducibility of replicate experiments and for modeling variation between different cellular contexts...
March 15, 2018: Bioinformatics
Chiara Nicoletti, Mattia Forcato, Silvio Bicciato
In all organisms, chromatin is packed to fulfil structural constraints and functional requirements. The hierarchical model of chromatin organization in the 3D nuclear space encompasses different topologies at diverse scale lengths, with chromosomes occupying distinct volumes, further organized in compartments, inside which the chromatin fibers fold into large domains and short-range loops. In the recent years, the combination of chromosome conformation capture (3C) techniques and high-throughput sequencing allowed probing chromatin spatial organization at the whole genome-scale...
March 15, 2018: Current Opinion in Biotechnology
Jinlei Han, Zhiliang Zhang, Kai Wang
It is well known that the chromosomes are organized in the nucleus and this spatial arrangement of genome play a crucial role in gene regulation and genome stability. Different techniques have been developed and applied to uncover the intrinsic mechanism of genome architecture, especially the chromosome conformation capture (3C) and 3C-derived methods. 3C and 3C-derived techniques provide us approaches to perform high-throughput chromatin architecture assays at the genome scale. However, the advantage and disadvantage of current methodologies of C-technologies have not been discussed extensively...
2018: Molecular Cytogenetics
Timothy J Stodola, Pengyuan Liu, Yong Liu, Andrew Vallejos, Aron M Geurts, Andrew S Greene, Mingyu Liang
A challenge to understanding enhancer-gene relationships is that enhancers are not always sequentially close to the gene they regulate. Physical proximity mapping through sequencing can provide an unbiased view of the chromatin close to the proximal promoter of the renin gene (Ren). Our objective was to determine genomic regions that physically interact with the renin proximal promoter, using two different genetic backgrounds, the Dahl salt sensitive and normotensive SS-13BN, which have been shown to have different regulation of plasma renin in vivo...
March 9, 2018: Physiological Genomics
Nolwenn Briand, Philippe Collas
The nuclear lamina contributes to the regulation of gene expression and to chromatin organization. Mutations in A-type nuclear lamins cause laminopathies, some of which are associated with a loss of heterochromatin at the nuclear periphery. Until recently however, little if any information has been provided on where and how lamin A interacts with the genome and on how disease-causing lamin A mutations may rearrange genome conformation. Here, we review aspects of nuclear lamin association with the genome. We highlight recent evidence of reorganization of lamin A-chromatin interactions in cellular models of laminopathies, and implications on the 3-dimensional rearrangement of chromatin in these models, including patient cells...
March 8, 2018: Nucleus
Martin Becker, Paolo Devanna, Simon E Fisher, Sonja C Vernes
Mutations of the FOXP2 gene cause a severe speech and language disorder, providing a molecular window into the neurobiology of language. Individuals with FOXP2 mutations have structural and functional alterations affecting brain circuits that overlap with sites of FOXP2 expression, including regions of the cortex, striatum, and cerebellum. FOXP2 displays complex patterns of expression in the brain, as well as in non-neuronal tissues, suggesting that sophisticated regulatory mechanisms control its spatio-temporal expression...
2018: Frontiers in Molecular Neuroscience
Robert-Jan Palstra, Elisa de Crignis, Michael D Röling, Thomas van Staveren, Tsung Wai Kan, Wilfred van Ijcken, Yvonne M Mueller, Peter D Katsikis, Tokameh Mahmoudi
We integrated data obtained from HIV-1 genome-wide association studies with T cell-derived epigenome data and found that the noncoding intergenic variant rs4349147, which is statistically associated with HIV-1 acquisition, is located in a CD4+ T cell-specific deoxyribonuclease I hypersensitive region, suggesting regulatory potential for this variant. Deletion of the rs4349147 element in Jurkat cells strongly reduced expression of interleukin-32 (IL-32), approximately 10-kb upstream, and chromosome conformation capture assays identified a chromatin loop between rs4349147 and the IL-32 promoter validating its function as a long-distance enhancer...
February 2018: Science Advances
Robert M Vaughan, Bradley M Dickson, Evan M Cornett, Joseph S Harrison, Brian Kuhlman, Scott B Rothbart
UHRF1 is a histone- and DNA-binding E3 ubiquitin ligase that functions with DNMT1 to maintain mammalian DNA methylation. UHRF1 facilitates DNMT1 recruitment to replicating chromatin through a coordinated mechanism involving histone and DNA recognition and histone ubiquitination. UHRF2 shares structural homology with UHRF1, but surprisingly lacks functional redundancy to facilitate DNA methylation maintenance. Molecular mechanisms uncoupling UHRF2 from DNA methylation maintenance are poorly defined. Through comprehensive and comparative biochemical analysis of recombinant human UHRF1 and UHRF2 reader and writer activities, we reveal conserved modes of histone PTM recognition but divergent DNA binding properties...
February 28, 2018: Nucleic Acids Research
Hidetoshi Kono, Shun Sakuraba, Hisashi Ishida
The eukaryotic genome is packaged into a nucleus in the form of chromatin. The fundamental structural unit of chromatin is a protein-DNA complex, the nucleosome, where 146 or 147 base pairs of DNA wrap 1.75 times around a histone core. To function in cellular processes, however, nucleosomal DNA must be unwrapped. Although this unwrapping has been experimentally investigated, details of the process at an atomic level are not yet well understood. Here, we used molecular dynamics simulation with an enhanced sampling method to calculate the free energy profiles for unwrapping the outer superhelical turn of nucleosomal DNA...
March 5, 2018: PLoS Computational Biology
Quentin Szabo, Daniel Jost, Jia-Ming Chang, Diego I Cattoni, Giorgio L Papadopoulos, Boyan Bonev, Tom Sexton, Julian Gurgo, Caroline Jacquier, Marcelo Nollmann, Frédéric Bantignies, Giacomo Cavalli
Deciphering the rules of genome folding in the cell nucleus is essential to understand its functions. Recent chromosome conformation capture (Hi-C) studies have revealed that the genome is partitioned into topologically associating domains (TADs), which demarcate functional epigenetic domains defined by combinations of specific chromatin marks. However, whether TADs are true physical units in each cell nucleus or whether they reflect statistical frequencies of measured interactions within cell populations is unclear...
February 2018: Science Advances
Chen Sun, Chang Lu
Detecting three-dimensional (3D) genome organization in the form of physical interactions between various genomic loci is of great importance for understanding transcriptional regulations and cellular fate. Chromosome Conformation Capture (3C) method is the gold standard for examining chromatin organization, but usually requires a large number of cells (>107 ). This hinders studies of scarce tissue samples from animals and patients using the method. Here we developed a microfluidics-based approach for examining chromosome conformation by 3C technology...
March 2, 2018: Analytical Chemistry
Jianfeng Wu, Sirui Yang, Di Yu, Wenjing Gao, Xianjun Liu, Kun Zhang, Xueqi Fu, Wanguo Bao, Kaiyu Zhang, Jiaao Yu, Liankun Sun, Shaofeng Wang
Genetic variants near the tumor necrosis factor-α-induced protein 3 gene (TNFAIP3) at the chromosomal region 6q23 demonstrated significant associations with multiple autoimmune diseases. The signals of associations have been explained to the TNFAIP3 gene, the most likely causal gene. In this study, we employed CRISPR/cas9 genome-editing tool to generate cell lines with deletions including a candidate causal variant, rs6927172, at 140 kb upstream of the TNFAIP3 gene. Interestingly, we observed alterations of multiple genes including IL-20RA encoding a subunit of the receptor for interleukin 20...
February 23, 2018: Genes and Immunity
Shalaka Chitale, Holger Richly
The integrity of the genome is maintained by specific DNA repair pathways. The main pathway removing DNA lesions induced by exposure to UV light is nucleotide excision repair (NER). The DNA damage response at chromatin is accompanied by the recruitment of DNA repair factors to the lesion site and the deposition of specific histone marks. The function of these histone marks in NER stays for the most part elusive. We have recently reported that the methyltransferase MMSET catalyzes the dimethylation of histone H4 at lysine 20 (H4K20me2) at the lesion site...
February 26, 2018: Nucleus
Mohammad Bozlur Rahman, Karl Schellander, Núria Llamas Luceño, Ann Van Soom
Currently, the world is facing the negative impact of global warming on all living beings. Adverse effects of global warming are also becoming obvious in dairy cattle breeding. In dairy bulls, low fertility has frequently been reported during summer season especially in tropical or subtropical conditions. Typically, spermatozoa at post-meiotic stages of development are more susceptible to heat stress. During this period extensive incorporation of histone modifications and hyperacetylation turns the chromatin into an unstable conformation...
February 12, 2018: Theriogenology
Qian Bian, Erika C Anderson, Katjuša Brejc, Barbara J Meyer
The function of chromatin modification in establishing higher-order chromosome structure during gene regulation has been elusive. We dissected the machinery and mechanism underlying the enrichment of histone modification H4K20me1 on hermaphrodite X chromosomes during Caenorhabditis elegans dosage compensation and discovered a key role for H4K20me1 in regulating X-chromosome topology and chromosome-wide gene expression. Structural and functional analysis of the dosage compensation complex (DCC) subunit DPY-21 revealed a novel Jumonji C demethylase subfamily that converts H4K20me2 to H4K20me1 in worms and mammals...
February 22, 2018: Cold Spring Harbor Symposia on Quantitative Biology
Michael Hausmann, Emma Wagner, Jin-Ho Lee, Gerrit Schrock, Wladimir Schaufler, Matthias Krufczik, Franziska Papenfuß, Matthias Port, Felix Bestvater, Harry Scherthan
Ionizing radiation (IR)-induced damage confers functional and conformational changes to nuclear chromatin associated with DNA single and double strand breaks. This leads to the activation of complex DNA repair machineries that aim to preserve the integrity of the DNA molecule. Since hetero- and euchromatin are differentially accessible to DNA repair pathways, local chromatin re-arrangements and structural changes are among the consequences of an activated DNA damage response. Using super-resolution localization microscopy (SRLM), we investigated the X-ray-induced repositioning of γ-H2AX and histone H3K9me3 heterochromatin marks in the nuclei of HeLa cells...
February 14, 2018: Nanoscale
Rubina Jibran, Helge Dzierzon, Nahla Bassil, Jill M Bushakra, Patrick P Edger, Shawn Sullivan, Chad E Finn, Michael Dossett, Kelly J Vining, Robert VanBuren, Todd C Mockler, Ivan Liachko, Kevin M Davies, Toshi M Foster, David Chagné
Black raspberry (Rubus occidentalis L.) is a niche fruit crop valued for its flavor and potential health benefits. The improvement of fruit and cane characteristics via molecular breeding technologies has been hindered by the lack of a high-quality reference genome. The recently released draft genome for black raspberry (ORUS 4115-3) lacks assembly of scaffolds to chromosome scale. We used high-throughput chromatin conformation capture (Hi-C) and Proximity-Guided Assembly (PGA) to cluster and order 9650 out of 11,936 contigs of this draft genome assembly into seven pseudo-chromosomes...
2018: Horticulture Research
Yanjian Li, Yi He, Zhengyu Liang, Yang Wang, Fengling Chen, Mohamed Nadhir Djekidel, Guipeng Li, Xu Zhang, Shuqin Xiang, Zejun Wang, Juntao Gao, Michael Q Zhang, Yang Chen
Chromatin conformation plays a key role in regulating gene expression and controlling cell differentiation. However, the whole-genome chromatin conformation changes that occur during leukemia cell differentiation are poorly understood. Here, we characterized the changes in chromatin conformation, histone states, chromatin accessibility, and gene expression using an all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation model. The results showed that the boundaries of topological associated domains (TADs) were stable during differentiation; however, the chromatin conformations within several specific TADs were obviously changed...
February 8, 2018: Cell Death & Disease
Petros Kolovos, Rutger W W Brouwer, Christel E M Kockx, Michael Lesnussa, Nick Kepper, Jessica Zuin, A M Ali Imam, Harmen J G van de Werken, Kerstin S Wendt, Tobias A Knoch, Wilfred F J van IJcken, Frank Grosveld
Chromosome conformation capture (3C) and its derivatives (e.g., 4C, 5C and Hi-C) are used to analyze the 3D organization of genomes. We recently developed targeted chromatin capture (T2C), an inexpensive method for studying the 3D organization of genomes, interactomes and structural changes associated with gene regulation, the cell cycle, and cell survival and development. Here, we present the protocol for T2C based on capture, describing all experimental steps and bio-informatic tools in full detail. T2C offers high resolution, a large dynamic interaction frequency range and a high signal-to-noise ratio...
March 2018: Nature Protocols
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